A green approach to the synthesis of 2,3-dihydropyrimidin-2(1H)-ones by uronium hydrogensulfate under solvent-free conditions

Article abstract of DOI:10.3987/COM-04-10312

3,4-Dihydropyrimidin-2(1H)-ones and -thiones are synthesized in high yields by a one-pot condensation of an aldehyde, a β-dicarbonyl compound with hydrogensulfate salt of urea or thiourea under solvent-free conditions.

Full text of DOI:10.3987/COM-04-10312

HETEROCYCLES, Vol. 65, No. 5, 2005
1177
HETEROCYCLES Vol.65, No.5, 2005, pp. 1177 - 1181
Received, 20th December, 2004, Accepted, 2nd March, 2005, Published online, 3rd March, 2005
A GREEN APPROACH TO THE SYNTHESIS OF
2,3-DIHYDROPYRIMIDIN-2(1H)-ONES BY URONIUM
HYDROGENSULFATE UNDER SOLVENT-FREE
CONDITIONS
Peyman Salehi,1,* Minoo Dabiri,2 Mohammad Ali Zolfigol,3 and
Mostafa Baghbanzadeh2
1. Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Evin, P.O.Box 19835-389,
Tehran, Iran, e-mail: p-salehi@sbu.ac.ir
2. Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Evin, Tehran, Iran
3. Department of Chemistry, Faculty of Science, Bu-Ali Sina University,
Hamadan, 65174, Iran
Abstract- 3,4-Dihydropyrimidin-2(1H)-ones and –thiones are synthesized in high
yields by a one-pot condensation of an aldehyde, a β-dicarbonyl compound with
hydrogensulfate salt of urea or thiourea under solvent-free conditions.
3,4-Dihydropyrimidin-2(1H)-ones and their sulfur analogues (Biginelli compounds, DHPMs) represent an
important heterocyclic system which are becoming increasingly sufficient due to their therapeutic and
pharmacological properties, such as antiviral, antibacterial, and hypertensive, as well as efficacy as potent
calcium channel blockers, α1a adrenergic antagonists, and neuropeptide Y(NPY) antagonists.1,2 Also the anti-
HIV activity in some marine natural products containing the DHMPs skeleton is observed.3
The Biginelli reaction, first described more than a centuryago, was a one-pot but low yielding (often 20-
50%) condensation of β-dicarbonyl compounds with aromatic aldehydes and urea under strongly acidic
conditions.4 Subsequent multistep syntheses produced somewhat higher yields but lacked the simplicity of
one-pot, one step synthesis.5
The art of performing efficient chemical transformation by coupling three or more components in a single
operation by a catalytic process avoiding stoichiometic toxic reagents, large amount of solvents and
expensive purification techniques, represents a fundamental target of modern organic synthesis.6 Thus
Biginelli’s reaction for the synthesis of dihydropyrimidinones has received renewed interest and several

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HETEROCYCLES, Vol. 65, No. 5, 2005
improved procedures have recently been reported.7-19 However some of these newer reported methods also
suffer from drawbacks such as unsatisfactory yields, cumbersome product isolation procedure, applicability
for only aromatic aldehydes, and environmental pollution.7-12, 19 Consequently, there are scopes for further
renovation toward milder reaction conditions, use of environmentally benign reagents, variations of
substituents in all three components, and better yields.
Herein, we describe a novel, green, and high yielding protocol for the preparation of 3,4-dihydropyrimidin-
2(1H)-ones and –thiones by the reaction of aromatic and aliphatic aldehydes with β-dicarbonyl compounds
in the presence of uronium- or thiouronium hydrogensulfate which act both as the substrate and the pormoter
(Scheme 1). Uronium hydrogensulfate is a very cheap and stable solid material that its application in
synthetic methodology has already been reported.20
O
R1
X
O
O
R3
Solvent-Free
65oC
+
NH
+
R1-CHO
+
R2
R3
NH3
H2N
-
R2
X
N
H
HSO4
X=O,S
Scheme 1
The reaction of various types of aldehydes and β-dicarbonyls with hydrogensulfate salt of urea- or -thiourea
under solvent-free conditions resulted in the formation of dihydropyrimidin-2-ones and -thiones. The
reactions proceeded smoothly at 65˚C and were completed within 2-4 hours. Table 1 shows the generality of
this protocol, which is equally effective for urea and thiourea, and also for aromatic and aliphatic aldehydes.
Under this condition, the yields were significantly better in comparison with the classical Biginelli
procedure. Several aromatic aldehydes carrying either electron-releasing or electron-withdrawing
substituents in the ortho-, meta- or para- positions afforded high yields of products. An important feature of
this procedure is the survival of a variety of functional groups such as alkoxy groups, nitro groups, hydroxy
groups, halogeno groups, etc. under the reaction conditions. Another advantage of this method is its
efficiency for the high yield synthesis of DHPMs from aliphatic aldehydes (Entries 12, 13). 3,4-
Dihydropyrimidin-2(1H)-thiones, which are also of interest because of their biological activities, are
synthesized with similar success. For example monastrol, a mitoic kinesin Eg5 motor portein inhibitor and
potential new lead for the development of anticancer drugs,21 was obtained in 91% yield (Entry 25) . A bis-
dihydropyrimidinone compound was also synthesized by a pseudo five-component reaction that could be an

HETEROCYCLES, Vol. 65, No. 5, 2005
1179
Table 1. Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and -thiones by the Condensation of
Aldehydes, β-Dicarbonyls and Uronium- or Thiouronium Hydrogensulfate under Solvent-Free
Conditions
Yielda
Mp(oC)b
Time
Entry
R1
R2
R3
X
(h)
2
(%)
93
92
96
92
91
96
95
89
90
90
96
91
89
91
93
94
92
95
83
87
81
90
91
93
90
92
85
45
Found
Reported
202-20419
206-20812
26215
227-22913a
164-1669
208-21119
213-21519
201-20319
185-18619
1787
232-2358
157-15816
151-1527
157-15919
209-21219
204-20719
235-23719
254-2558
168-17019
233-23618
168-1709
230(dec)8
209-21111
203-20513a
184-18616
1
2
C6H5
2-NO2-C6H4
2-CH3O-C6H4
3-O2N-C6H4
3-HO-C6H4
4-O2N-C6H4
4-Cl-C6H4
4-CH3O-C6H4
4-F-C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
Me
O
205-207
207-209
261-263
223-225
161-163
209-211
212-214
203-204
185-187
176-177
231-233
157-159
150-153
155-158
208-210
205-207
235-236
250-253
165-168
237-238
166-167
231(dec)
208-211
206-208
185-186
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
2.5
2
3
4
3
5
3
6
3
7
3.5
2.5
3
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28c
3,4-(CH3O)2-C6H3
C6H5-CH=CH
n-C3H7
2
2
2
n-C6H13
2
C6H5
4
C6H5
2
4-Cl-C6H4
4-O2N-C6H4
2,4-(Cl)2-C6H3
4-CH3O-C6H4
C6H5
3
3
2.5
3
2
4-CH3O-C6H4
4-O2N-C6H4
C6H5
Me
3
Me
3
OEt
OEt
OEt
Me
2
3-O2N-C6H4
3-HO-C6H4
C6H5
S
3
S
3
S
2
187(dec) 185(dec)17
4-CHO-C6H4
C6H5
OEt
OEt
O
O
4
>290
>30014
202-20419
6
205-207
a
Isolated yield (65oC).
b
Products were characterized by comparison of their spectroscopic data (1H-NMR and IR spectrum) and mps with those
reported in the literature.
c
The reaction was performed in the absence of uronium hydrogensulfate

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HETEROCYCLES, Vol. 65, No. 5, 2005
interesting model compound for new generation of biologically active molecules (Entry 27). Entry 28 shows
the promotion effect of uronium hydrogensulfate in the Biginelli reaction.
In conclusion, we have described a highly efficient solvent-free modification of the Biginelli
multicomponent reaction that allows the assembly of structurally divers DHPM derivatives. Mild reaction
conditions, high yields, elimination of solvent or solid support, and the stability and cheapness of the reagent
are features of this new procedure. The work-up procedure is very simple and green, including washing the
reaction mixture with water followed by recrystallization of the product from EtOH. Another advantage of
this environmentally benign and safe protocol is the use of uronium and thiouronium hydrogensulfate that
acts as both the promoter and the source of one of the substrates. Moreover, this method has the ability to
tolerate a wide variety of substituents in all three components.
EXPERIMENTAL
Products are known compounds and were characterized by comparison IR and 1HNMR spectra and melting
points were essentially identical with those of authentic samples. Melting points were measured on an
Electrothermal 9100 apparatus and are not corrected. IR spectra were measured on a Shimadzu IR-470
spectrophotometer. 1HNMR spectra were run on a Bruker 500 DRX AVNCE spectrometer. Yields refer to
isolated products.
General procedure for the synthesis of DHPMs
Aldehyde (1 mmol), the β-dicarbonyl compound (1 mmol), urea (or thiourea) (0.5 mmol), and uronium (or
thiouronium) hydrogensulfate (1 mmol), were thoroughly mixed and heated at 65oC under solvent-free
conditions for the appropriate period of time (Table 1). After completion of the reaction as indicated by TLC
analysis, the solid mixture was washed with cold water (15 mL) to remove the excess of urea or thiourea and
also the acidic reagent and then filtered. The remaining crude product was recrystallized from EtOH.
ACKNOWLEDGEMENT
We are grateful to the Research Council of Shahid Beheshti University for partial support of this project.
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